Metastasis is the primary cause of death in cancer patients. Particularly aggressive forms of cancer, such as pancreatic ductal adenocarcinoma or basal-like breast cancer, are highly lethal in part due to their tendency to metastasize, often prior to diagnosis. Metastatic tumors are often characterized by intrinsic resistance to traditional chemo- and radiotherapies, making them an important target for the development of novel therapies.
Not all cancer cells within a primary tumor drive metastasis. Instead, only a small subsection of the tumor cell population, called cancer stem cells (CSCs), are capable of initiating metastasis and the formation of novel tumors. CSC subtypes have been identified in breast, pancreatic, prostate, colon, brain and liver cancers, as well as leukemias and are inherently resistant to chemo- and radiotherapy which target proliferating cells. Unfortunately, monotherapy with cytotoxic agents actually have been found to enhance the relative proportion of CSC cells within a tumor. The CSCs are then capable of reestablishing tumors post-therapy, leading to the generation of novel masses characterized by cancer cell populations with increased drug resistance and enhanced metastatic ability.
The acquisition of CSC properties is closely associated with the activation of the “epithelial-to-mesenchymal transition” (“EMT”) and concomitant expression surface markers notable in highly aggressive and invasive cancers. The ability of a tumor cell to acquire CSC characteristics and form metastasis seems to be due in part to the EMT. However, EMT is also a requirement for normal development and repair mechanisms such as embryogenesis, and fibrosis and wound healing, and in all cases entails morphological and phenotypic changes to cells.
A number of proteins and transcription factors have been found to induce EMT, such as, but not limited to, various transcription factors and hormones. The altered expression of these factors can thus affect the status of EMT, and hence, embryonic development, fibrosis and wound healing, and the development of cancer.
EMT is regulated in part at a post-transcriptional level via miRNAs. miRNAs are small, non-coding RNAs that regulate translation on a post-transcriptional level by causing mRNA degradation or repressing mRNA translation. miRNAs and mature miRNAs can function as oncogenes and are differentially expressed in cancer versus healthy cells.
One particular miRNA, miRNA-221, is significantly upregulated in a large number of cancers, and its expression characterizes the most aggressive forms of human solid tumors. The overexpression of miRNA-221, sometimes by up to 70-fold compared to healthy tissue, has been documented in hepatocarcinoma, non-small cell lung cancer, pancreatic, melanoma, breast, thyroid and multiple myeloma, among others (Cancer Cell 16:498-509 (2009)). As used herein, the terms “overexpression” or “elevated expression” means more than 2-fold. miRNA 221 as well as miRNA 222 also function as regulators of the EMT in basal-like breast cancers and have multiple targets, at least two of which function to modulate the EMT pathway.
Gene expression includes transcription of the DNA to RNA, and the translation of RNA into proteins and peptides. Controlling the expression of certain genes in a cell is a useful tool for increasing or inhibiting the growth of cells, and for increasing and inhibiting the synthesis of certain desired native or genetically engineered cellular products such as those involved in the production of beneficial enzyme and hormone synthesis or which are cancer markers.
One method of treating cancer uses antisense methodology. Antisense technology is another example of a known method of controlling the expression of cellular DNA whereby a synthesized oligonucleotide synthesized to have a particular sequence complementary to a portion of that of a targeted DNA is used to bind that DNA, thereby stopping the target DNA it from being duplicated or from being transcribed into RNA. However, this technology has not been very efficacious as many antisense oligonucleotides have difficulty crossing cell members and so are never able to contact and bind to their target oligonucleotide. In addition, antisense molecules are not targeted to one particular molecule as they can bind to both DNA and RNA having complementary nucleotide sequences and thus may have affinity for more than one target sharing that particular sequence.
Thus, what are needed are improved compositions and therapeutic methods for more specific regulation of RNA expression.
In addition, therapeutic methods and pharmaceutical compositions that can inhibit the growth of cancer and in particular, can inhibit the development of metastasis-inducing cancer stem cells are needed.